In order to obtain drug efficacy by administering a drug, an oral administration method is generally used; however, transdermal administration method has many advantages compared to oral administration method. For example, in oral administration method, a drug absorbed in the bowel is first metabolized in the liver so that a large amount of the drug is decomposed before it exhibits drug efficacy in desired regions; whereas in transdermal administration method, the absorbed drug does not pass initially through the liver in the body circulation, and therefore its efficacy is not significantly decreased in the liver due to metabolism. Furthermore, transdermal administration method has other advantages such as, at the drug effect is continuous, and it has a sustained drug release characteristics.
In addition, as an advantage of transdermal administration method, reduction of side effects can be expected by sustained release of drugs and by maintaining their constant blood levels in particular, there is a tendency that transdermal administration preparations that can be administered for a long period of time (1 day to 7 days) are desired from the viewpoint of patient compliance.
In such percutaneous absorption preparations, an important issue is how to effectively release the drug (medicinal ingredient) from a base, namely, to effectively transfer the drug from the base to the skin. In general, when formulation design is attempted using a specific drug, quite often crystallization, etc. occurs due to insufficient dissolution of the drug in a base, resulting in a decreased level of drug release and insufficient therapeutic effect. In addition, crystallization is undesirable from the viewpoint of long-term storage of preparations. Accordingly, selection of a crystallization inhibitor is important for percutaneous absorption preparations. Furthermore, because a drug is absorbed through the skin, it is necessary to increase the skin permeability of the drug. Therefore, selection of the optimal dissolving agent for the drug is important in the formulation design; depending on the selection of dissolving agent, dissolution of the drug becomes insufficient, leading to a decreased level of release of the drug from the base and decreased level of transfer of the drug to a diseased part, and consequently, sufficient therapeutic effect cannot be exerted.
Imidafenacin (4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutane amide) is a muscarinic receptor antagonist having a M3 and M1 muscarinic receptor antagonistic activity selective for the bladder, and is a therapeutic drug for urinary frequency and urinary incontinence.
While imidafenacin has been used as an agent for oral administration in the current clinical setting, from the viewpoints of reduction of side effects such as liver failure, stabilization of blood concentration for a long period of time, and long-sustaining effects, development of transdermal administration preparations such as adhesive patch, etc., rather than oral administration preparations, has been desired.
Based on such current situation, percutaneous absorption preparations comprising imidafenacin have been proposed (Patent Literatures 1 and 2).
In Patent Literatures 1 and 2, a percutaneous absorption preparation comprising 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutane amide (imidafenacin) is described; however, since imidafenacin has low skin permeability, in order to use it in a skin-absorption type preparation wherein a drug is efficiently absorbed through the skin, it is necessary to increase its skin permeability and to suppress crystallization. However, in Patent Literatures 1 and 2, a means for solving such problems has not been provided.
In Patent Literature 3, an adhesive patch composed of a backing and an adhesive layer comprising a free-basic drug, an adhesive agent and a fatty acid having an aliphatic hydrocarbon group with a carbon number of 8-22; however, this does not provide a means for solving the problem of inhibiting the crystallization simultaneously without decreasing the skin permeability in percutaneous absorption preparations comprising imidafenacin as the therapeutic agent for urinary frequency and urinary incontinence.